Abstract

Objective

This study investigates the predictive value of systemic inflammatory indices for repeat transuretral resection of bladder tumour (Re-TUR-BT) pathology in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

Materials and Methods

We conducted a retrospective analysis of 83 patients diagnosed with primary bladder tumors who underwent Re-TUR-BT based on initial pathology results from January 2014 to December 2023. Patients were categorized into two groups based on Re-TUR-BT pathology: Group 1 (non-malignant at Re-TUR-BT) and group 2 (malignant at Re-TUR-BT). We compared systemic inflammatory markers between these groups.

Results

Of the 83 patients, 55 (82.5%) were in group 1 and 28 (17.5%) in group 2. Demographic characteristics showed no significant differences between the groups. However, upon comparison of operative and histopathological features, the incidence of T1 classification in first TUR-BT pathology, was significantly higher in group 2. Additionally, group 1 had a higher proportion of single tumors, whereas group 2 exhibited a greater incidence of two or more tumors, a difference that was statistically significant. Analysis of systemic inflammatory indices revealed no significant differences in the complete blood count results before the initial TUR-BT. However, both the systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR) showed significant differences before Re-TUR-BT.

Conclusion

Our study indicates that SII and NLR calculated prior to Re-TUR-BT can predict malignant pathology persistence in high-risk NMIBC patients. These findings underscore the potential of systemic inflammatory indices as valuable biomarkers in clinical practice.

Introduction

Bladder cancer (BC) is categorized into two main subtypes: Non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), based on their clinical progression and prognosis. The standard treatment approach for NMIBC primarily consists of transurethral resection of the bladder tumour (TUR-BT), followed by intravesical instillation of either chemotherapy or immunotherapy, tailored to the patient’s risk of disease recurrence and progression. To mitigate the risk of understaging that can occur during the initial TUR-BT, clinical guidelines recommend performing a second resection (Re-TUR-BT) within 4 to 6 weeks following the initial procedure (1). The rationale behind Re-TUR-BT is to prevent understaging of NMIBC, to remove any residual cancer that may have been overlooked during the first procedure, and to provide additional prognostic data. The incidence of understaging in NMIBC cases ranges from approximately 7% to 30%, and this figure can rise to as high as 45% when the initial TUR-BT specimen lacks detrusor muscle (2). The incidence of understaging in NMIBC cases is reported to range from approximately 7% to 30%. This percentage can increase to as much as 45% when the initial TUR-BT specimen does not contain detrusor muscle (2). Additionally, a recent study found that among 31 patients with T1 high-grade tumors, there was a high rate of Re-TUR-BT positivity, recorded at 58.5 % (3).

Despite patients achieving complete resection of NMIBC and undergoing adjuvant intravesical instillation therapy, it is noted that approximately 70% of them will experience disease recurrence. Furthermore, around 30% of these individuals may ultimately face disease progression (4). Recent studies have explored various prognostic models and biomarkers as potential predictors of BC recurrence to enhance clinical decision-making and patient counseling (5). Indeed, while the identification of biomarkers for BC has the potential to enhance prognostic accuracy and treatment personalization, several challenges have impeded their integration into routine clinical practice. High costs associated with these biomarkers, along with a lack of standardization across different laboratories and methods, have limited their widespread adoption.

The relationship between the body’s inflammatory response and the development of cancer, including BC, has garnered significant attention in recent years. The connection between inflammation and tumors was first observed by Virchow in 1863 (6). Inflammation not only contributes to malignant transformation and metastasis but also forms an integral part of the tumor’s local environment (7).

Emerging evidence indicates that inflammatory responses within the tumor microenvironment (TME) are crucial in BC tumorigenesis, proliferation, progression, and metastasis. The immune system, together with the inflammatory response and the TME, significantly influences the clinical and biological behavior and outcomes of BC (7).

Researchers have extensively investigated the prognostic value of inflammatory response markers in cancer through ratios such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, and systemic immune-inflammation index (SII). These markers have been studied for their potential to predict cancer prognosis, offering insights into the complex interactions between inflammation and cancer dynamics (8).

To the best of our knowledge, no studies have specifically evaluated inflammatory indices for predicting Re-TUR-BT outcomes, despite their prognostic value in other BC contexts. In our study, we explored the relationship between inflammation indices and the likelihood of malignant pathology results in patients undergoing Re-TUR-BT for high-risk BC. Inflammatory indices may be important predictors of malignant pathology outcomes in patients undergoing Re-TUR-BT for high-risk BC, and their assessment may improve preoperative evaluation and treatment decision-making.

Materials and Methods

Ethics Statement

This research was carried out in accordance with the ethical guidelines established in the Declaration of Helsinki. All participants received comprehensive information regarding the study’s objectives and provided their written informed consent. The Local Ethics Committee of Health Science University İstanbul Training and Research Hospital granted ethical approval for this study (approval number: 2024-97, date: 18.10.2024).

Study Design

In this study, we conducted a retrospective analysis of patients diagnosed with primary bladder tumors who underwent Re-TUR-BT operation based on their initial pathology results. The objective of the study was to investigate the predictive role of inflammatory indexes in assessing the likelihood of malignant pathology results within this high-risk patient cohort.

Selection of Participants

The study participants were high grade NMIBC patients who underwent Re-TUR-BT operation between January and December 2023. Patients with concomitant malignancies, a history of upper urinary tract transitional cell carcinoma, rheumatic diseases, prior cardiac surgery, and chronic renal failure were excluded from the analysis. A total of 83 patients who met the inclusion criteria were retrospectively analyzed (Figure 1).

Study Variables

Routine complete blood count measurements were obtained from all patients scheduled to undergo initial TUR-BT, diagnosed with primary bladder tumors, and from patients requiring Re-TUR-BT based on the findings of the initial pathology. These measurements were analyzed for the purpose of calculating systemic inflammatory indices. The time interval from the first operation to the second was recorded in days. The NLR, lymphocyte-to-monocyte ratio (LMR), PLR, monocyte-to-white blood cell ratio (MWR), SII, and systemic inflammatory response index (SIRI) were calculated using the following formulas: NLR = neutrophil/lymphocyte ratio; LMR = lymphocyte/monocyte ratio; PLR = platelet/lymphocyte ratio; MWR = monocyte/white blood cell ratio; SII = (neutrophil × platelet)/lymphocyte ratio; SIRI = (neutrophil × monocyte)/lymphocyte ratio.

At the commencement of the first operation, data regarding tumor size, number, and appearance type (papillary or solid) were retrospectively reviewed and utilized for analysis. Pathology specimens obtained from both the initial and Re-TUR-BT procedures were evaluated by the same pathologist at a single pathology clinic. Patients were categorized into two groups based on the pathology results of the Re-TUR-BT operation. The absence of any tumour detected on re-TURB was considered non-malignant, while the detection of Ta/T1 high-grade or carcinoma in situ (CIS) was considered malignant (group 1: Non-malignant at Re-TUR-BT, group 2: Malignant at Re-TUR-BT). Values were compared for both groups (Figure 1).

Statistical Analysis

Descriptive statistics were calculated for demographic and clinical characteristics. Continuous variables were expressed as median and interquartile range while categorical variables were expressed as frequencies and percentages. Mann-Whitney U test was used to compare non-normally distributed continuous variables, and chi-square tests were employed for categorical variables. The chi-square test was employed to analyze categorical data. A significance level of p<0.05 was established for all analyses.All statistical analyses were performed using SPSS version 28.0. Furthermore, a separate receiver operating characteristic (ROC) analysis was conducted to calculate the area under the curve (AUC) for distinguishing malignant pathology within each group.

Results

After applying the exclusion criteria, the study population was stratified into two groups based on the pathology results from the Re-TUR-BT operation. Group 1 consisted of 55 patients with non-malignant pathology findings, while group 2 included 28 patients with malignant pathology results.

The comparison of the demographic characteristics of the two groups is summarized in Table 1. There were no statistically significant differences in terms of age, gender, body mass index, smoking status, or comorbid conditions between the groups (p>0.05, for each).

According to the results of initial TUR-BT pathology, forty (48.2%) of the patients had pTa high-grade pathology and 43 (51.8%) had pT1 high-grade pathology. In addition, 24 (28.9%) had concomitant CIS.

The comparison of the groups in terms of operative and histopathological features is summarised in Table 2. There were no statistically significant differences between the two groups regarding the presence of concomitant carcinoma in situ, tumor size, tumor characteristics (papillary or solid), and time to the second TUR-BT. However, the number of patients with initial TUR-BT pathology classified as T1 was significantly higher in group 2 (p<0.05). Additionally, group 1 exhibited a higher proportion of single tumors, whereas group 2 showed a greater proportion of two or more tumors (p<0.05).

The results of the comparison of the systemic inflammatory indices between the two groups are summarized in Table 3. There was no significant difference between the groups regarding the SII calculated from complete blood count results before the initial TURB. However, both the SII and the NLR showed statistically significant differences in the systemic inflammatory indices before Re-TUR-BT in group 2 (p=0.017 and p=0.029, respectively).

The SII values measured before the Re-TUR-BT operation demonstrated significant efficacy in differentiating between non-malignant and malignant pathology, with an AUC of 0.660 [95% confidence interval (CI): 0.538-0.783; p=0.010] as illustrated in Figure 1. Additionally, the NLR values obtained prior to the Re-TUR-BT were also significant, demonstrating diagnostic value in predicting malignant pathology. This was confirmed through ROC analysis, yielding an AUC of 0.647 (95% CI: 0.524-0.770; p=0.020), as shown in Figure 2.

Discussion

The SII, a composite marker derived from peripheral blood counts, has garnered increasing attention in recent years due to its prognostic utility across various medical fields. Studies have demonstrated its relevance not only in oncology but also in cardiovascular diseases, autoimmune disorders, and infectious diseases, where systemic inflammation plays a critical role in disease pathophysiology and progression (3, 9). The ability of SII to reflect the dynamic balance between immune activation and suppression positions it as a potentially valuable tool in clinical decision-making, especially in oncology. Its accessibility, cost-effectiveness, and reproducibility make it an attractive option for risk stratification and patient management across diverse clinical contexts (10, 11). While the role of SII in oncology (particularly in predicting outcomes in malignancies such as bladder cancer) has been well documented, emerging evidence suggests that SII may also serve as a valuable biomarker in the diagnosis, monitoring, and prognostication of various cancers. This underscores its potential to enhance clinical practice by improving patient outcomes through more tailored management strategies.

In this single-center retrospective study, we examined the clinical significance of preoperative blood-based systemic inflammatory indices in patients with high-risk NMIBC who required Re-TUR-BT. Our findings demonstrated that elevated levels of the SII and NLR were independent predictive factors for malignant pathology in Re-TUR-BT specimens. This suggests that these inflammatory markers may serve as valuable tools in the preoperative assessment and risk stratification of patients undergoing Re-TUR-BT for high-risk NMIBC.

Numerous recent studies have highlighted the benefits of Re-TUR-BT in patients with high-risk NMIBC (3, 12). This procedure improves diagnostic precision and aids in the removal of any remaining cancerous tissue. A recent meta-analysis that included 29 studies found a combined prevalence of 56% for residual tumors and 10% for upstaging to T2 among 3,566 and 2,556 patients, respectively (13). The pathology results from Re-TUR-BT hold significant prognostic value and are deemed the most important predictor of early recurrence and progression. Herr and Donat (14) reported that the presence of T1 tumors at second-look TUR-BT is associated with a progression rate of 76% within five years. Palou and colleagues conducted an analysis involving a cohort of 2,451 patients to investigate the prognostic significance of pathology findings from second-look TUR-BT. Their study established that T1 tumors identified during the second-look TUR-BT were associated with a higher likelihood of recurrence, progression, and mortality due to the disease. In a multivariate model that included factors such as tumor multiplicity, concomitant CIS, and BCG maintenance, second-look TUR-BT pathology emerged as the most critical prognostic factor for these outcomes (15).

Additionally, the therapeutic benefits of Re-TUR-BT have been noted. Comparisons between second-look TUR-BT and observation have shown significantly lower recurrence rates at 3 to 6 months post-cystoscopy for both T1 and high-grade Ta tumors (16). A recent study indicated that patients who underwent second-look TUR-BT had statistically significant improvements in cancer-specific survival (CSS) (p=0.009) and overall survival (p<0.001) compared to those who did not (17).

In this study, we aimed to identify the factors that may serve as predictors of tumor persistence following the initial TUR-BT. Specifically, we focused on patients’ cohort whose tumors were found to be persistent based on the pathological findings from the subsequent Re-TUR-BT procedure. Our investigation involved a comprehensive analysis of various biochemical, pathological, and demographic variables that could potentially influence the likelihood of tumor persistence.

Tumor-related factors, including pathological tissue type, grade, and stage, are critical for predicting the progression and prognosis of cancer patients. These factors provide essential insights into the biological behavior of tumors, enabling clinicians to stratify patients according to their risk of recurrence and progression. In our study, we observed that the number of patients whose initial TUR-BT pathology was classified as T1 was significantly higher in group 2. These findings align with those of Divrik et al. (2), who conducted a prospective randomized trial involving T1 patients undergoing either a single TUR-BT or a second TUR-BT. They reported 5-year recurrence-free survival rates of 32% and 59%, respectively, and noted that 33% of patients had residual tumor at the time of the second TUR-BT. Additionally, our study revealed a higher incidence of single tumors in group 1, while group 2 exhibited a greater prevalence of multifocal tumors. Previous research has supported these results, for example, Ferro et al. (18) identified a statistically significant association between the presence of T1 high-grade BC at Re-TUR-BT and factors such as multifocality, tumor size greater than 3 cm, and the presence of CIS at the first TURB. Furthermore, Kamiya et al. (19) demonstrated that multifocality at the first TUR-BT is an independent predictor of high-grade T1, at Re-TUR-BT. In our study, although we noted a higher rate of tumor diameter exceeding 3 cm and the presence of concomitant CIS in group 2, these differences did not reach statistical significance. According to a recent study, the primary distinctions between patients with and without T1 high grade tumors at Re-TUR-BT were related to the size of the main lesion and multifocality. Notably, 13.9% of patients lacked a muscle layer, and 15.1% presented with CIS; however, the differences between those with and without T1 high grade at Re-TUR-BT were not significant (20).

In addition to these tumor-related factors, patient-related elements also play a crucial role in predicting cancer outcomes. One such area of interest is the assessment of systemic inflammatory indices (21). Inflammatory mechanisms, initiated by substances such as chemokines and cytokines, are essential for supporting the proliferation and persistence of cancer cells through several pathways, including the stimulation of blood vessel formation and the enhancement of metastatic spread. At the same time, the activation of oncogenes initiates inflammatory pathways from within the cancer cells themselves. This relationship underscores the significant connection between inflammation and cancer, as inflammatory responses can foster an environment that supports the development and advancement of tumors (22).

Our results identified the SII and NLR as two significant systemic inflammatory indices that can predict malignant pathology following Re-TUR-BT operations. The SII has been established as an independent prognostic indicator for patients with BC undergoing radical cystectomy (RC) or TUR-BT. A comprehensive meta-analysis conducted by Li et al. (23), which included ten studies, found that elevated SII levels are associated with markedly decreased overall survival rates, CSS rates, and recurrence-free survival rates in BC patients. These findings also highlighted a considerable degree of heterogeneity across the studies. Furthermore, prior studies have demonstrated a correlation between adverse prognosis in BC and the NLR. The report by Mari et al. (24) highlighted that elevated preoperative NLR levels were independently linked to increased overall mortality in BC patients following RC. Additionally, a previous study has also found  that high NLR is associated with high grade disease (25). An increased NLR indicates a relative increase in neutrophils, which release inflammatory factors and specific proteases that induce extracellular matrix remodeling. This creates a favorable microenvironment for tumor cell migration and progression (26). The results imply that SII and NLR appear to be valuable biomarkers in assessing the prognosis and potential outcomes of patients with BC, especially in relation to surgical interventions.

We further analyzed the diagnostic value of inflammatory indices in Re-TUR-BT pathology and calculated the AUC from ROC curves. Our findings indicate that SII and NLR possess diagnostic utility for predicting malignant pathology. According to established literature, an AUC value between 0.7 and 0.8 is considered acceptable, while values between 0.6 and 0.7 are regarded as poor, and values below 0.6 indicate no diagnostic ability (27). Although both SII and NLR, assessed prior to re-TURBT, demonstrate some diagnostic value for identifying malignant pathology, their AUC values fall within the range of 0.6 to 0.7. This suggests that while these indices can provide insights, their diagnostic capability for predicting malignant pathology is limited.

Study Limitations

To highlight some important strengths of our study, to our knowledge, this is the first investigation in the literature exploring the value of systemic inflammatory indices for predicting pathology outcomes following Re-TUR-BT. Furthermore, all surgical procedures were conducted at a single center by a uro-oncological surgeon who specializes in bladder cancer, and the pathology results were interpreted by a single pathologist with expertise in urooncology. This consistency in both surgical technique and pathological evaluation enhances the quality and reliability of our findings, suggesting that single-center research can provide valuable insights. Despite the strengths of the study, several limitations warrant acknowledgment. First, the small sample size associated with a single-institute study may restrict the generalizability of the findings. Secondly, the retrospective cohort design could introduce selection bias, and the reliance on existing medical records for data collection may result in underreporting of comorbidities. This underreporting could significantly impact the validity of the results, as unrecognized comorbid conditions may confound the relationship between the variable of interest and the observed outcomes.  The other potential limitation of this study is the lack of multivariate analysis, which may have overlooked the influence of confounding variables on the observed outcomes. Additionally, the modest AUC values observed in our analysis suggest that the diagnostic power of the tested model is limited. This indicates that while the model may have some utility in distinguishing between conditions, its overall accuracy and reliability in a clinical setting may not be sufficient to warrant widespread application. Finally, the study did not assess several important inflammation-and nutrition-based indicators, such as the Glasgow prognostic score, the albumin/globulin ratio, and the C-reactive protein/albumin ratio. Including these metrics could have provided deeper insights into the relationship between systemic inflammation and patient outcomes. Given these limitations, we recommend larger, multicenter prospective cohort studies to confirm the preliminary results of this investigation and further evaluate the prognostic value of systemic inflammatory indices in high-risk NMIBC patients.

Conclusion

Our study shows that SII and NLR calculated before Re-TUR-BT have potential predictive values in detecting the persistence of malignant pathology in Re-TUR-BT among high-risk NMIBC patients. These findings highlight the potential utility of these systemic inflammatory indices as biomarkers in clinical practice. Given the significance of our results, we advocate for larger, multicenter studies to further validate these findings. Such research would enhance our understanding of the role of SII and NLR, helping to establish their potential as reliable tools for clinical decision-making in the management of high-risk NMIBC patients.